U.S. patent number 9,687,482 [Application Number 14/608,560] was granted by the patent office on 2017-06-27 for stable pharmaceutical composition comprising solifenacin, and method for preparing the same.
This patent grant is currently assigned to CJ HEALTHCARE CORPORATION. The grantee listed for this patent is CJ HEALTHCARE CORPORATION. Invention is credited to Young Dae Cho, Ha Yong Choi, Sung Kyun Han, Chun Seon Lyu, Young Hee Suh, Mi Young Yoon.
United States Patent |
9,687,482 |
Suh , et al. |
June 27, 2017 |
Stable pharmaceutical composition comprising solifenacin, and
method for preparing the same
Abstract
The present invention relates to a solifenacin preparation
containing solifenacin or a pharmaceutically acceptable salt
thereof, an antioxidant, and a binder, which is manufactured via
direct compression. Compared to the preparations manufactured via
conventional wet granulation process, the preparation of the
present invention can be manufactured by a simplified process such
as direct compression, and has improved content uniformity, mixing
degree, etc., even when the preparation is manufactured by high
speed tableting.
Inventors: |
Suh; Young Hee (Seoul,
KR), Cho; Young Dae (Osan-si, KR), Lyu;
Chun Seon (Yongin-si, KR), Yoon; Mi Young
(Cheonan-si, KR), Choi; Ha Yong (Yongin-si,
KR), Han; Sung Kyun (Hwaseong-si, KR) |
Applicant: |
Name |
City |
State |
Country |
Type |
CJ HEALTHCARE CORPORATION |
Seoul |
N/A |
KR |
|
|
Assignee: |
CJ HEALTHCARE CORPORATION
(Seoul, KR)
|
Family
ID: |
52449981 |
Appl.
No.: |
14/608,560 |
Filed: |
January 29, 2015 |
Prior Publication Data
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|
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Document
Identifier |
Publication Date |
|
US 20150216856 A1 |
Aug 6, 2015 |
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Foreign Application Priority Data
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Feb 3, 2014 [KR] |
|
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10-2014-0012121 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
9/2054 (20130101); A61K 9/2095 (20130101); A61K
47/10 (20130101); A61K 31/439 (20130101); A61P
13/00 (20180101); A61K 31/4725 (20130101); A61P
13/02 (20180101); A61K 47/38 (20130101); A61P
13/10 (20180101); A61P 11/02 (20180101); A61P
11/06 (20180101); A61P 43/00 (20180101); A61P
11/00 (20180101) |
Current International
Class: |
A61K
31/4725 (20060101); A61K 47/10 (20170101); A61K
31/439 (20060101); A61K 47/38 (20060101); A61K
9/20 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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104739789 |
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Jul 2015 |
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CN |
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2 018 850 |
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Jan 2009 |
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EP |
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2 500 013 |
|
Sep 2012 |
|
EP |
|
1020070010132 |
|
Jan 2007 |
|
KR |
|
1020070098889 |
|
Oct 2007 |
|
KR |
|
1020120093500 |
|
Aug 2012 |
|
KR |
|
2008/128028 |
|
Oct 2008 |
|
WO |
|
2009/012987 |
|
Jan 2009 |
|
WO |
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2010/097243 |
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Sep 2010 |
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WO |
|
Primary Examiner: Shterengarts; Samantha
Attorney, Agent or Firm: Seed IP Law Group LLP
Claims
The invention claimed is:
1. A solifenacin tablet prepared via direct compression, comprising
solifenacin or a pharmaceutically acceptable salt thereof, an
antioxidant, and a binder, wherein the binder is contained in the
amount from 0.0292 part by weight to 0.3 part by weight relative to
total weight of the tablet.
2. The solifenacin tablet of claim 1, wherein the antioxidant is
contained in the amount from 0.01 part by weight to 0.04 part by
weight relative to 1 part by weight of the solifenacin or a
pharmaceutically acceptable salt thereof.
3. The solifenacin tablet of claim 1, wherein the antioxidant is
butylhydroxytoluene or butylhydroxyanisol.
4. The solifenacin tablet of claim 1, wherein the binder is
low-substituted hydroxypropyl cellulose.
5. The solifenacin tablet of claim 1, wherein the binder is
contained in the amount from 25 parts by weight to 300 parts by
weight relative to 1 part by weight of the antioxidant.
6. The solifenacin tablet of claim 5, wherein the binder is
contained in the amount from 50 parts by weight to 200 parts by
weight relative to 1 part by weight of the antioxidant.
7. The solifenacin tablet of claim 1, wherein the binder is
contained in the amount from 0.4 part by weight to 10 parts by
weight relative to 1 part by weight of the solifenacin or a
pharmaceutically acceptable salt thereof.
8. The solifenacin tablet of claim 1, further comprising a
disintegrating agent, a lubricant or a coating agent.
9. A method for manufacturing solifenacin tablet, comprising:
mixing solifenacin or a pharmaceutically acceptable salt thereof,
an antioxidant and a binder; and tableting the mixture via direct
compression, wherein the binder is contained in the amount from
0.0292 part by weight to 0.3 part by weight relative to total
weight of the tablet.
10. The method of claim 9, wherein the mixture does not comprise a
solvent.
Description
TECHNICAL FIELD
The present invention relates to a stable preparation containing
solifenacin, and a method of manufacturing the same.
BACKGROUND ART
Solifenacin is a compound represented by Chemical Formula 1 below
and is reported to have an excellent selective antagonistic action
against muscarinic M3 receptors.
##STR00001##
Meanwhile, although solifenacin or a pharmaceutically acceptable
salt thereof may be stable in the state of a raw material, there is
a problem with the drug in that it decomposes with time due to
various factors involved in the process of manufacturing it into a
final product. As a representative example, an amorphous form of
solifenacin succinate is generated during the process of wet
granulation and easily oxidized within a short period. In
particular, the main degradation product (an oxidized form of
solifenacin succinate) has been reported to be the major cause of
the decomposition problems of the main drug. That is, it is
difficult to develop a desirable formulation and process due to
drug instability problems which may occur, depending on various
process conditions such as reaction temperature, pH, reaction time,
order of mixing, etc., or by interactions occurring when
excipients, binders, lubricants, etc. are combined and come in
contact with the active ingredient, depending on the
characteristics of exipients, etc.
Additionally, the cohesiveness of solifenacin or a pharmaceutically
acceptable salt thereof complicates the formulation process. KR
Patent Application Publication No. 10-2007-0010132 discloses that
it is preferred that any formulations containing solifenacin or a
pharmaceutically acceptable salt thereof be manufactured via a wet
granulation process because the content uniformity of solifenacin
or a pharmaceutically acceptable salt thereof is difficult to
ensure via direct compression and also they tend to adhere to the
punch during the compression process.
Accordingly, commercial formulations on the market such as
Vesicare.RTM. containing solifenacin succinate are manufactured via
a wet granulation process, and various methods have been suggested
to improve the stability of such formulations. For example, KR
Patent Application Publication No. 10-2007-0010132 discloses, as a
method of preventing the time-based decomposition of a drug in
solifenacin succinate-containing formulation, a method of
controlling the percentage of the amorphous form in the formulation
to a certain amount or lower, thereby preventing the time-based
decomposition, or controlling the water content contained in the
formulation during manufacture, heat treatment and/or humidity
treatment after manufacture, thereby lowering the content of the
amorphous form. Additionally, the above KR Patent Application
Publication No. 10-2007-0010132 discloses that, at the time of
manufacturing a formulation containing solifenacin or its salt, the
amorphization of solifenacin can be prevented by using a binder
such as polyethylene glycol (PEG), thereby manufacturing a
formulation capable of inhibiting the time-based decomposition.
Additionally, KR Patent Application Publication No. 10-2007-0098889
discloses that, in manufacturing a granular pharmaceutical
composition containing solifenacin or a pharmaceutically acceptable
salt thereof, the stability of the main component can be secured by
using a binder having a Tg of 174.degree. C. or below.
As described above, due to the strong cohesiveness of solifenacin
or a pharmaceutically acceptable salt thereof as a raw material and
its instability during the formulation process, it is very
difficult to select a suitable formulation method. The
previously-suggested methods may provide a certain degree of
stability but the water content contained in the granules during
the wet granulation process is affected by various conditions
during the manufacturing process such as reaction time, order of
mixing, etc., and thus controlling the percentage of the amorphous
form to a certain amount or lower by adjusting the water content is
very unlikely to improve the stability of the formulation when this
method is applied to large-scale production.
Additionally, in the case of manufacturing a formulation via a wet
granulation method, the main components generally tend to exhibit
time-based decomposition due to their interaction with water or
organic solvents such as alcohol, and due to heat treatment for the
purpose of removing the solvents.
Additionally, there are also limitations in the methods of
preventing the time-based decomposition of solifenacin via
selection and utilization of a specific binder for the wet
granulation method due to the instability of the wet method. In
particular, polyethylene oxide, which was suggested as one of the
binders, has incompatibility with a strong oxidant (Handbook of
Pharmaceutical excipients, 4.sup.th edition), and in addition, when
lactose or mannitol is mixed with polyethylene oxide, the release
behavior of the drug may vary over the course of its storage life,
and thus its incompatibility was disclosed by a publication
released by DOW company during the CRS conference in 2008 (KR
Patent Application Publication No. 10-2012-0093500). Accordingly,
considering that polyethylene oxide limits the selectable scope of
the main excipients, with the combined use of polyethylene oxide is
not desirable.
Therefore, there is still a high demand for the development of a
novel preparation capable of preventing the time-based
decomposition of solifenacin or its salt while also providing easy
control over the preparation process in a commercial production
environment.
DISCLOSURE
Technical Problem
Accordingly, the present invention has been made keeping in mind
the above problems occurring in the prior art, and an objective of
the present invention is to provide a preparation capable of
preventing the time-based decomposition of solifenacin or a
pharmaceutically acceptable salt thereof while also providing easy
control over the preparation process in a commercial production
environment.
Additionally, another objective of the present invention is to
provide a preparation which can be manufactured via direct
compression instead of a wet granulation process, and a method of
manufacturing the same.
Technical Solution
In order to accomplish the above objectives, the present invention
provides a solifenacin preparation comprising solifenacin or a
pharmaceutically acceptable salt thereof, an antioxidant, and a
binder.
As used herein, the term `solifenacin` refers to a compound with
the chemical name of
(1R,3'R)-3'-quinuclidinyl-1-phenyl-1,2,3,4-tetrahydro-2-isoquinoline
carboxylate [IUPAC name: 1-azabicyclo[2.2.2]oct-3-yl
(1R)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate] as
represented by Chemical Formula 1 below.
##STR00002##
Solifenacin has been reported to have an excellent selective
antagonistic action against muscarinic M3 receptors, and also is
effective as a therapeutic agent for the prevention and treatment
of urosis such as nervous pollakiuria, neurogenic bladder,
nocturnal enuresis, unstable bladder, bladder contracture or
chronic cystitis, and respiratory diseases such as chronic
obstructive pulmonary disease, chronic bronchitis, asthma,
rhinitis, etc.
Additionally, as used herein, the term `pharmaceutically acceptable
salt` refers to an acid added salt with an inorganic acid such as
hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid,
nitric acid, phosphoric acid, etc. or an organic acid such as
formic acid, acetic acid, propionic acid, oxalic acid, malonic
acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic
acid, citric acid, tartaric acid, carbonic acid, picric acid,
methanesulfonic acid, ethanesulfonic acid, glutamic acid, etc.; or
a quaternary ammonium salt. Among them, succinate of solifenacin is
desirable as a commercial drug and it is also preferable because it
can be considerably stabilized by the present invention.
The present invention relates to a solifenacin preparation capable
of inhibiting the time-based decomposition of solifenacin or its
pharmaceutically acceptable salt while also providing easy control
over the preparation process in a commercial production
environment. Due to the high cohesiveness of solifenacin, the
conventional wet granulation method has been used for securing
content uniformity, but the wet granulation method cannot
fundamentally resolve the problem of solifenacin decomposition
because of the high sensitivity of solifenacin to water. In this
regard, the present invention includes an antioxidant and a binder
as constituting components of the solifenacin preparation, and thus
is capable of securing content uniformity by direct compression
instead of a wet granulation method, and also of fundamentally
resolving the problem of the decomposition of solifenacin, which is
sensitive to water.
As used herein, the term `antioxidant` refers to a substance which
inhibits the decomposition of solifenacin in a pharmaceutical
preparation, and specifically, butylhydroxytoluene or
butylhydroxyanisol may be used. Preferably, the antioxidant is used
in the amount from 0.01 part by weight to 0.04 part by weight
relative to 1 part by weight of solifenacin or a pharmaceutically
acceptable salt thereof. When the amount is less than 0.01 part by
weight, the amount of the main degradation product of solifenacin
(hereinafter referred to as F1) relative to the total amount of
solifenacin as an active ingredient and the degradation products
cannot be maintained at a level of 0.5% or less, whereas when it
exceeds 0.04 part by weight it can be toxic to the human body.
According to an embodiment of the present invention (Examples 1
through 7), at the time of manufacturing the preparation via direct
compression, when the preparation includes an antioxidant to
maintain stability of solifenacin, the degradation products of
solifenacin was significantly reduced.
As used herein, the term `binder` refers to a substance which
provides a binding force to a solifenacin preparation, in
particular, hydroxypropyl cellulose, gums, hydroxypropyl
methylcellulose, polyvinylpyrrolidone, low-substituted
hydroxypropyl cellulose, starch, lactose and a hydrate thereof,
microcrystalline cellulose and ethylcellulose may be used. More
preferably, low-substituted hydroxypropyl cellulose may be used.
The low-substituted hydroxypropyl cellulose (L-HPC) used in the
present invention refers to hydroxypropyl cellulose containing from
5% to 16% of hydroxypropoxy group. Due to the water-insolubility of
low-substituted hydroxypropyl cellulose, when it contacts an
aqueous solution it tends to swell, thereby providing a binding
force during the direct compression method. Additionally, due to
the swelling phenomenon, it is expected to have the indirect
function of a disintegrating agent. Additionally, L-HPC has
different particle sizes depending on the substitution level and
thus L-HPC having the desired particle size may be selected to
provide a binding force in the direct compression method.
Preferably, the binder is contained in the amount from 0.4 part by
weight to 10 parts by weight relative to 1 part by weight of
solifenacin or a pharmaceutically acceptable salt thereof. When the
binder is contained in an amount less than 0.4 part by weight, the
binding force during the tableting process becomes too weak to
allow compression, or the prepared products may have low hardness,
resulting in tablet fracture during the manufacturing process or
other tablet defects seriously compromising their merchantability,
thereby lowering production efficiency. Additionally, when the
binder content exceeds 10 parts by weight, the in vivo dissolution
pattern of the drug may not meet the requirement of bioequivalence
in comparison with the commercial tablet products on the market,
thus lowering the practicability of the corresponding
solifenacin-containing tablet. Additionally, the binder is
preferably contained in the amount from 25 parts by weight to 300
parts by weight relative to 1 part by weight of the antioxidant.
More preferably, the binder is contained in the amount from 50
parts by weight to 200 parts by weight relative to 1 part by weight
of the antioxidant. When the content ratio of the binder and the
antioxidant are not within the above ranges, the stability of
solifenacin may not be guaranteed or the problems of the direct
compression method, e.g., content uniformity variations, may not be
resolved.
As described above, the addition of the antioxidant and the binder
as the constituting components of the solifenacin preparation can
prevent generation of related substances or impurities and allow
the solifenacin preparation to be formulated via a direct
compression method, and also can provide a dissolution pattern
equivalent to those of the commercial products.
According to an embodiment of the present invention (Examples 8
through 11), the solifenacin preparation containing the antioxidant
and the binder showed a significant decrease in its mass deviation
even when manufactured via direct compression. Additionally,
according to an embodiment of the present invention (Example 12),
the solifenacin preparation containing the antioxidant and the
binder showed a significant content uniformity similar to the level
of preparations manufactured via a wet granulation method. From the
above, it was confirmed that the addition of the antioxidant and
the binder as constituting ingredients of the solifenacin
preparation could solve the problems existing in the conventional
solifenacin preparations manufactured via a wet granulation
method.
Additionally, the solifenacin preparation may further include a
pharmaceutically acceptable disintegrating agent, lubricant or
coating agent insofar as the inclusion thereof would not alter the
effects of the present invention. The coating agent may form a film
layer on the external surface of the solifenacin preparation, e.g.,
a light-shielding film layer, a moisture-proofing film layer, a
sugar film layer, etc. The external film layer is preferably formed
by a water-soluble material. Examples of the material for forming
the water-soluble film layer may include hydroxypropyl
methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose,
cellulose acetate phthalate, ethylcellulose, methylcellulose,
polymethacrylate, polyvinyl alcohol (Opadry.RTM.; Colorcon, USA),
and mixtures thereof, but not limited thereto.
Additionally, considering the pharmaceutically acceptable daily
dose of solifenacin or a pharmaceutically acceptable salt thereof,
the amount of solifenacin or a pharmaceutically acceptable salt
thereof contained in the solifenacin preparation may be from 0.01
mg to 100 mg, preferably from 0.5 mg to 50 mg, more preferably from
0.5 mg to 20 mg, most preferably from 0.5 mg to 10 mg.
Additionally, the present invention provides a method for
manufacturing a solifenacin preparation comprising the following
steps of:
mixing solifenacin or a pharmaceutically acceptable salt thereof,
an antioxidant and a binder (step 1); and
tableting the mixture (step 2).
Generally, it is highly likely that the manufacture of preparations
with a smaller proportion of main components by a direct
compression method may cause problems of weight deviation or
content uniformity among tablets. In particular, in the case of a
main component such as solifenacin which has low stability, factors
related to the stability of the main components should also be
considered and thus it is very difficult to find an optimal method
of manufacturing a preparation suitable for the characteristics of
solifenacin as a main component.
The present invention, by including the antioxidant and the binder,
provides a stable composition not generating drug degradation
products or causing a decrease of drug content even when employing
the direct compression method, while meeting the standards for
content uniformity prescribed in the Revision of the Regulatory
Provision for Review of Request on Specifications and Test
Procedures of Drugs (Notification No. 2007-47 of the Korean
Ministry of Food and Drug Safety, Jul. 2, 2007) and the Korean
Pharmacopoeia (10.sup.th Edition). The manufacture of a preparation
by the direct compression method according to the present invention
is simpler than that by the wet granulation method and is thus
advantageous for a large-scale process. As such, the above method
of manufacturing the solifenacin preparation is characterized in
that it does not include a solvent.
Examples of the pulverizer used in the process for preparing a
stable pharmaceutical composition containing solifenacin or a salt
thereof may include a hammer mill, a ball mill, a jet miller, a
colloid mill, a motor-driven mesh, an oscillator, a co-mill, etc.,
but may not be particularly limited, and any device or means
capable of pulverizing from the conventional, pharmaceutical aspect
may be used.
A mixing device for each component used subsequently to the
pulverization may include a V-type mixer, a ribbon-type mixer, a
container mixer, a high speed agitator mixer, etc., but may not be
particularly limited, and any device or means capable of uniformly
mixing each component from the conventional, pharmaceutical aspect
may be used.
Examples of tablet press machines may include rotary tablet press
machines, single tablet press machines, etc., but they are not
particularly limited, and any conventional pharmaceutical device or
means capable of manufacturing compressed products (more
appropriately, tablets) will be sufficient.
Advantageous Effects
According to the present invention, a solifenacin preparation
containing solifenacin or a pharmaceutically acceptable salt
thereof, an antioxidant, and a binder can be rapidly manufactured
via a simplified direct compression method, and the
thus-manufactured solifenacin preparation has excellent stability.
Additionally, although the main components have high cohesiveness,
the percentage of the main components in the preparation is low,
and the preparation is manufactured via a direct compression
method, the preparation, by including the antioxidant and the
binder, is advantageous in that it has excellent content uniformity
and is free of problems of weight deviation.
DESCRIPTION OF DRAWINGS
FIG. 1A and FIG. 1B respectively show the results of a dissolution
test between the compositions of Examples 8 through 11 according to
the present invention and the control drug (Vesicare.RTM. tablet),
and the results of a dissolution test between the composition of
Example 12, the composition of Comparative Example 3 and the
control drug (Vesicare.RTM. tablet).
FIG. 2 shows the results of a dissolution test between the
composition of Example 13 according to the present invention and
the control drug (Vesicare.RTM. tablet, 10 mg).
MODE FOR INVENTION
The present invention will be explained in greater detail through
the following examples and experimental examples as set forth
herein below, but they are disclosed for illustrative purposes only
and are not to be construed as limiting the scope of the limit of
the present invention.
EXAMPLE 1
For the manufacture of tablets, 16.65 g of solifenacin succinate,
0.5 g of butylhydroxytoluene, and 100.0 g of lactose were mixed by
trituration and then filtered through a 30-mesh sieve (trituration
mixing-1). Subsequently, 50.0 g of microcrystalline cellulose and
325.35 g of lactose hydrate were mixed, and filtered through a
30-mesh sieve (trituration mixing-2).
The trituration mixtures 1 and 2 were mixed in a 1 kg mixer (erweka
AR 402/cubemixer) at 200 rpm for 15 minutes, and the resulting
mixture was lubricated and mixed with 7.5 g of magnesium stearate,
filtered through a 30-mesh sieve, and then formed into circular
tablets using a single tablet press machine (erweka AR 401). The
content of each component of the thus-obtained tablets is shown in
Table 1 below.
TABLE-US-00001 TABLE 1 Mixing Purpose Composition (grade) Weight %
per Tablet Excipient lactose 20.00 Active Ingredient solifenacin
succinate 3.33 Disintegrating Agent microcrystalline cellulose
10.00 Excipient lactose hydrate 65.07 Antioxidant
butylhydroxytoluene 0.10 Lubricant magnesium stearate 1.50 Total
Weight (%) 100.00
EXAMPLES 2 THROUGH 7 AND COMPARATIVE EXAMPLE 1
In order to evaluate the degree of generation of related substances
or impurities, or unknown materials by the addition of an
antioxidant in the composition, tablets with the compositions of
Examples 2 through 7 and Comparative Example 1 were
manufactured.
For the manufacture of tablets with the compositions of Examples 2
through 7 and Comparative Example 1, 16.65 g of solifenacin
succinate, butylhydroxytoluene (varying from 0.25 g to 0.5 g
depending on Examples 2 through 7), 100.0 g of lactose hydrate and
50.0 g of microcrystalline cellulose were mixed by trituration, and
then filtered through a 30-mesh sieve (trituration mixing-1).
Subsequently, 100.0 g of microcrystalline cellulose and lactose
hydrate (varying from 212.35 g to 212.85 g depending on Example 2
through 7 and Comparative Example 1), and then filtered through a
30-mesh sieve (trituration mixing-2).
The trituration mixtures 1 and 2 were mixed in a 1 kg mixer (erweka
AR 402/cubemixer) at 200 rpm for 15 minutes, and the resulting
mixture was lubricated and mixed with 7.5 g of magnesium stearate,
filtered through a 30-mesh sieve, and then formed into circular
tablets using a single tablet press machine (erweka AR 401). The
thus-completed core tablets were coated with Opadry.RTM. (yellow,
opadry 03B52293). The content of each component of the
thus-obtained tablets is shown in Table 2 below.
TABLE-US-00002 TABLE 2 Comp. Composition Ex. 2 Ex. 3 Ex. 4 Ex. 5
Ex. 6 Ex. 7 Ex. 1 Lactose 20.00 20.00 20.00 20.00 20.00 20.00 20.00
Solifenacin 3.33 3.33 3.33 3.33 3.33 3.33 3.33 Succinate
Microcrystalline 10.00 10.00 10.00 10.00 10.00 10.00 10.00
Cellulose (Trituration mixing-1) Microcrystalline 20.00 20.00 20.00
20.00 20.00 20.00 20.00 Cellulose (Trituration mixing-2) Lactose
Hydrate 42.47 42.52 42.56 42.47 42.52 42.56 42.57
Butylhydroxytoluene 0.10 0.05 0.01 -- -- -- -- Butylhydroxyanisol
-- -- -- 0.10 0.05 0.01 -- Magnesium Stearate 1.50 1.50 1.50 1.50
1.50 1.50 1.50 Opadry .RTM. (Yellow) 2.60 2.60 2.60 2.60 2.60 2.60
2.60 Total Weight (%) 100 100 100 100 100 100 100
EXAMPLES 8 THROUGH 12 AND COMPARATIVE EXAMPLES 2 AND 3
In order to evaluate content uniformity and dissolution pattern of
preparations according to the present invention, tablets with the
compositions of Example 8 through 11 and Comparative Example 2 were
manufactured.
16.65 g of solifenacin succinate, 0.5 g of butylhydroxytoluene,
low-substituted hydroxypropyl cellulose (varying from 0.0 g to
150.0 g depending on the respective composition of Examples 8
through 11 and Comparative Example 2) and 95.0 g of isomalt were
mixed by trituration, and filtered through a 30-mesh sieve
(trituration mixing-1).
Subsequently, 10.0 g of hydrophobic colloidal silicon dioxide and
lactose hydrate (varying from 207.35 g to 357.35 g depending on
Examples 8 through 11 and Comparative Example 2) were mixed, and
filtered through a 30-mesh sieve (trituration mixing-2).
The trituration mixtures 1 and 2 were mixed in a 1 kg mixer (erweka
AR 402/cubemixer) at 200 rpm for 15 minutes, and the resulting
mixture was lubricated and mixed with 7.5 g of magnesium stearate,
filtered through a 30-mesh sieve, and then formed into circular
tablets using a single tablet press machine (erweka AR 401). The
thus-completed core tablets were coated with Opadry.RTM. (yellow,
opadry 03B52293). The content of each component of the
thus-obtained tablets is shown in Table 3 below.
TABLE-US-00003 TABLE 3 Comp. Composition Ex. 8 Ex. 9 Ex. 10 Ex. 11
Ex. 2 Solifenacin 3.33 3.33 3.33 3.33 3.33 Succinate
Butylhydroxytoluene 0.10 0.10 0.10 0.10 0.10 Hydrophobic 2.00 2.00
2.00 2.00 2.00 Colloidal Silicon Dioxide Low-Substituted 5.00 10.00
20.00 30.00 0.00 Hydroxypropyl Cellulose Isomalt 19.00 19.00 19.00
19.00 19.00 Lactose Hydrate 66.47 61.47 51.47 41.47 71.47 Magnesium
Stearate 1.50 1.50 1.50 1.50 1.50 Opadry .RTM. (Yellow) 2.60 2.60
2.60 2.60 2.60 Total Weight (%) 100 100 100 100 100
Additionally, for the manufacture of tablets according to Example
12 and Comparative Example 3, 16.65 g of solifenacin succinate, 0.5
g of butylhydroxytoluene, low-substituted hydroxypropyl cellulose
(varying from 0.0 g to 15.0 g depending on Example 12 and
Comparative Example 3), lactose hydrate (varying from 18.35 g to
33.35 g depending on Example 12 and Comparative Example 3) and
33.35 g of isomalt were mixed by trituration, and filtered through
a 30-mesh sieve (trituration mixing-1).
Subsequently, 5.0 g of hydrophobic colloidal silicon dioxide and
388.15 g of lactose were mixed and filtered through a 30-mesh sieve
(trituration mixing-2).
The trituration mixtures 1 and 2 were mixed in a 1 kg mixer (erweka
AR 402/cubemixer) at 200 rpm for 15 minutes, and the resulting
mixture was lubricated and mixed with 10.0 g of sodium stearyl
fumarate, filtered through a 30-mesh sieve, and then formed into
circular tablets using a single tablet press machine (erweka AR
401). The thus-completed core tablets were coated with Opadry.RTM.
(yellow, opadry 03B52293). The content of each component of the
thus-obtained tablets is shown in Table 4 below.
TABLE-US-00004 TABLE 4 Composition Ex. 12 Comp. Ex. 3 Lactose
Hydrate 3.67 6.67 Hydrophobic Colloidal Silicon 1.0 1.0 Dioxide
Solifenacin Succinate 3.33 3.33 Low-Substituted 3.00 --
Hydroxypropyl Cellulose Butylhydroxytoluene 0.10 0.10 Isomalt 6.67
6.67 Lactose 77.63 77.63 Sodium Stearyl Fumarate 2.0 2.0 Opadry
.RTM. (Yellow) 2.60 2.60 Total Weight (%) 100 100
EXAMPLE 13
In order to evaluate the dissolution of solifenacin
succinate-containing preparations with different constitutional
contents of solifenacin succinate, tablets with the composition of
Example 13 were manufactured. The manufacturing process was the
same as in Example 12, and the content of each component of the
thus-obtained tablets is shown in Table 5 below.
TABLE-US-00005 TABLE 5 Composition Ex. 13 Solifenacin succinate
6.49 Butylhydroxytoluene 0.10 Hydrophobic colloidal silicon dioxide
2.92 Low-substituted hydroxypropyl cellulose 2.92 Isomalt 19.48
Lactose hydrate 64.03 Magnesium stearate 1.46 Opadry .RTM. (pink)
2.60 Total weight (%) 100
EXPERIMENTAL EXAMPLE 1
Evaluation of Stability According to Composition of
Preparations
Solifenacin succinate-containing preparations manufactured in
Examples 1 through 7 and Example 8 containing a binder were packed
in PVC, PVDC, and HDPE containers conventionally used in the art,
stored under severe stability conditions (60.degree. C./relative
humidity 80%), and the change in related substances at initial
stage, after 1 week, 2 weeks, and 4 weeks of storage were analyzed.
Vesicare.RTM. 5 mg coated tablets on the market were used as a
control drug, and stability test was performed under the same
condition.
The standard of related substances or impurities in solifenacin
succinate as a raw material was applied to this Example, and the
detailed standard and items are shown in Table 6 below.
TABLE-US-00006 TABLE 6 Related Substances or Impurities Standard
YM-64250 .ltoreq.1.1% (+)-(1S,3'R)-1'-oxidoquinuclidin-3'-yl-1-
phenyl-1,2,3,4-tetrahydroisoquinoline-2- carboxylate YM 217880
.ltoreq.0.5% (+)-(R)-quinuclidin-3-yl
[2-(2-benzoylphenyl)ethyl]carbamate Unknown Related Substances or
Impurities .ltoreq.0.2% Total of Related Substances or Impurities
.ltoreq.2.0%
The change in the related substances or impurities was analyzed via
high performance chromatography (Agilent) and the HPLC conditions
used are as follows.
Detector: UV spectrophotometer (wavelength for measurement: 215
nm)
Column: XBridge.TM. C18, 150.times.4.6 mm, 5.0 .mu.m or a column
equivalent thereof
Flow rate: 1.0 mL/min
Column temperature: a constant temperature around 35.degree. C.
Amount of injection: 20 .mu.L
Range of measurement: 1) for 40 minutes after injecting a test
solution 2) for 20 minutes after injecting a standard solution
Mobile phase: buffer solution*/methanol=35/65
Diluent: mobile phase
*buffer solution: 3.4 g of dipotassium monohydrogen phosphate was
well dissolved in 1000 mL of water, added with 1.0 mL of
trifluoroacetic acid, and adjusted to a pH of 7.5 by using
triethylamine. The resulting solution was filtered through a 0.45
.mu.m filter and deaerated to be used.
The evaluation results on the stability are shown in Table 7
below.
TABLE-US-00007 TABLE 7 Under Severe Stress Under Severe Stress
Under Severe Stress Related Condition for 1 Week Condition for 2
weeks Condition for 4 weeks Substances Initial Bottle PVC PVDC
Bottle PVC PVDC Bottle PVC PVDC Category or Impurities Standard
stage (%) (%) (%) (%) (%) (%) (%) (%) (%) Control YM-64250
.ltoreq.1.1% ND* 0.59 1.07 0.48 1.03 1.33 0.59 1.12 1.63 - 0.57
Drug YM 217880 .ltoreq.0.5% ND ND 0.55 0.25 0.71 0.96 0.43 0.80
0.96 1.78 (Vesicate .RTM., Other .ltoreq.0.2% ND ND ND ND ND 0.13
ND ND 0.28 ND 5 mg) respective impurities total .ltoreq.2% ND 0.59
1.62 0.73 1.74 2.42 1.02 1.52 2.87 2.35 Ex. 1 YM-64250 .ltoreq.1.1%
ND ND ND ND 0.05 0.38 0.36 0.07 0.74 0.75 YM 217880 .ltoreq.0.5% ND
ND ND ND 0.01 0.16 0.16 0.03 0.36 0.37 Other .ltoreq.0.2% ND ND ND
ND ND ND ND ND ND ND respective impurities total .ltoreq.2% ND ND
ND ND 0.06 0.54 0.52 0.10 1.1 1.12 Ex. 2 YM-64250 .ltoreq.1.1% ND
ND ND ND 0.14 ND ND 0.67 ND ND YM 217880 .ltoreq.0.5% ND ND ND ND
0.26 ND ND 0.61 ND ND Other- .ltoreq.0.2% ND ND ND ND ND ND ND ND
ND ND respective impurities total .ltoreq.2% ND ND ND ND 0.4 ND ND
1.28 ND ND Ex. 3 YM-64250 .ltoreq.1.1% ND ND ND ND ND ND ND 0.59 ND
ND YM 217880 .ltoreq.0.5% ND ND ND ND ND 0.12 ND 0.81 ND ND Other
.ltoreq.0.2% ND ND ND ND ND ND ND ND ND ND respective impurities
total .ltoreq.2% ND ND ND ND ND 0.12 ND 1.4 ND ND Ex. 4 YM-64250
.ltoreq.1.1% ND 0.24 0.4 ND ND 0.25 ND 0.67 0.57 0.69 YM 217880
.ltoreq.0.5% ND 0.08 0.17 ND ND 0.43 0.11 0.78 0.26 0.42 Other
.ltoreq.0.2% ND ND ND ND ND ND ND ND ND ND respective impurities
total .ltoreq.2% ND 0.32 0.31 ND ND 0.68 0.11 1.45 0.83 1.11 Ex. 5
YM-64250 .ltoreq.1.1% ND ND ND ND ND ND ND ND ND ND YM 217880
.ltoreq.0.5% ND ND ND ND ND ND ND ND ND ND Other .ltoreq.0.2% ND ND
ND ND ND ND ND ND ND ND respective impurities Total .ltoreq.2% ND
ND ND ND ND ND ND ND ND ND Ex. 6 YM-64250 .ltoreq.1.1% ND ND ND ND
ND ND ND ND ND ND YM 217880 .ltoreq.0.5% ND ND ND ND ND ND ND ND ND
ND Other .ltoreq.0.2% ND 0.03 ND ND ND ND ND ND ND ND respective
impurities Total .ltoreq.2% ND 0.03 ND ND ND ND ND ND ND ND Ex. 7
YM-64250 .ltoreq.1.1% ND ND ND ND ND 0.06 ND ND ND ND YM 217880
.ltoreq.0.5% ND ND ND ND ND 0.17 ND ND ND ND Other .ltoreq.0.2% ND
0.03 ND ND ND ND ND ND ND ND respective impurities Total .ltoreq.2%
ND 0.03 ND ND ND 0.25 ND ND ND ND Ex. 8 YM-64250 .ltoreq.1.1% ND ND
ND ND 0.04 0.27 0.24 0.07 0.35 0.37 YM 217880 .ltoreq.0.5% ND ND ND
ND 0.02 0.11 0.12 0.05 0.41 0.39 Other .ltoreq.0.2% ND ND ND ND ND
0.01 ND ND 0.05 0.02 respective impurities Total .ltoreq.2% ND ND
ND ND 0.07 0.39 0.36 0.12 0.81 0.78 Comp. YM-64250 .ltoreq.1.1% ND
0.23 1.35 0.42 0.36 1.36 0.94 1.41 1.88 1.0- 8 Ex. 1 YM 217880
.ltoreq.0.5% ND 0.40 1.06 0.35 0.56 1.21 0.80 0.89 1.37 1.- 10
Other .ltoreq.0.2% ND 0.49 0.13 ND ND ND ND ND 0.29 ND respective
impurities Total .ltoreq.2% ND 1.12 2.54 0.77 0.92 2.57 1.74 2.3
3.25 2.18
In the case of the preparation of Example 1, although it was a core
tablet, all of its contents and the levels of related substances
satisfied the standard requirement and remained stable until the
4.sup.th week of severe stress conditions regardless of their
packing materials. However, in the case of the control drug, the
related substance YM-64250 failed to meet the standard in PVC
packing (under 1 to 4 weeks of severe stress conditions) and HDPE
(4 weeks) materials, and the related substance YM-217880 failed to
meet the standard in PVC packing (under 1 to 4 weeks of severe
stress conditions) HDPE (2 and 4 weeks), and PVDC (4 weeks)
materials.
In the case of the preparation of Example 2, the presence of the
related substance YM-64250 was detected in HDPE container until the
2.sup.nd and 4.sup.th week of the severe stress conditions, but the
detected level was lower than that of control drugs on the market
and satisfied the standard requirement.
Overall, it was confirmed that antioxidants, butylhydroxytoluene
and butylhydroxyanisol used in Examples 1 through 7 improved the
stability of solifenacin succinate. Additionally, in the
preparation of tablets with the composition of Example 8 containing
an antioxidant and a binder, it was also confirmed that the level
of the related substances satisfied the standard requirement.
However, in the case of the preparation of Comparative Example 1
and the control drug not containing an antioxidant, the levels of
the related substances or impurities, or the unknown related
substances of solifenacin succinate were shown very high.
Accordingly, it was confirmed that the solifenacin
succinate-containing preparations according to the present
invention were very effectively prevented from generating the
related substances and also had an excellent stability compared to
that of the control drug.
EXPERIMENTAL EXAMPLE 2
Evaluation of Dissolution Rate According to Compositions of
Preparations
The dissolution rates of the solifenacin succinate-containing
preparations according to the present invention were evaluated by
comparing with those of the control drug (Vesicare.RTM., 5 mg). The
conditions applied in the evaluation of the dissolution rates are
as follows.
Manufacturer of Dissolution Apparatus and Test solution sampling
Apparatus: Agilent technologies
Model name of Dissolution Apparatus: 708-DS
Model name of Test solution sampling Apparatus: Dissolution
sampling station
Test solution sampling method: Auto sampling according to time
passage
Dissolution method: the Korean Pharmacopoeia (10.sup.th Edition),
the 2.sup.nd method (paddle speed: 50 rpm)
Time for collecting test solution: 5, 10, 15, 30 (and 45 min)
Number of tested materials: 4 tablets
Dissolution medium: Purified water and pH 6.8 phosphate buffer
Temperature of Dissolution medium: 37.5.degree. C..+-.0.5
Dissolution Apparatus: UV Spectrophotometer (wavelength for
measurement: 210 nm).
Column: Develosil ODS-UG-5 (150 mm.times.4.6 mm ID, Nomura Chemical
Co., Ltd.) or a column equivalent thereof
Column temperature: 40.degree. C.
Mobile phase: 0.05 mol/L potassium phosphate buffer (pH
6.0)/acetonitrile mixture (65:35)
Flow rate: 1.0 mL/min (adjusted to maintain the retention time of
solifenacin to be between 7 min to 11 min)
Test Period: About 12 min
As a result of the experiment, the dissolution rate of each
preparation in the phosphate buffer at pH 6.8 was as shown in Table
8.
TABLE-US-00008 TABLE 8 Dissolution Comp. Control Time (min) Ex. 8
Ex. 9 Ex. 10 Ex. 11 Ex. 2 Drug 5 22.5 .+-. 5.4 18.4 .+-. 4.7 15.9
.+-. 2.4 12.1 .+-. 6.2 29.8 .+-. 1.4 26.3 .+-. 4.0 10 43.8 .+-. 2.8
39.9 .+-. 2.3 37.5 .+-. 2.2 30.4 .+-. 2.9 56.7 .+-. 9.8 50.9 .+-.
5.8 15 64.5 .+-. 2.1 60.7 .+-. 2.2 58.5 .+-. 1.2 49.7 .+-. 3.8 83.6
.+-. 8.7 69.6 .+-. 8.1 30 84.1 .+-. 1.6 81.1 .+-. 1.6 77.6 .+-. 0.8
68.6 .+-. 4.4 93.8 .+-. 5.1 89.6 .+-. 2.5 45 89.4 .+-. 1.1 87.3
.+-. 1.5 84.7 .+-. 1.1 82.8 .+-. 3.1 107.5 .+-. 5.0 93.7 .+-.
2.4
From the results of Examples 8 through 11, it was confirmed that
the greater the amount of a binder, the lower the dissolution rate.
In the case of the preparation of tablets according to the
composition of Example 11, its dissolution rate, at 30 minutes,
fell short of 80% of that of the control drug, the drug on the
market, and thus it is not suitable for a release profile of a
solifenacin-containing preparation, which requires a fast release,
in terms of biological equivalence (according to the Notification
No. 2013-201 of the Korean Ministry of Food and Drug Safety, when
the average dissolution rate of a drug on the market (reference
drug) reaches 85% between 15 min and 30 min, if the average
dissolution rate of a drug to be compared (test drug) is within
that of the reference drug .+-.15% at two different time points
where the average dissolution rate of the reference drug is around
60% and 85%, respectively, they can be determined as having
equivalence). Additionally, it is also not suitable considering
there is a large deviation in terms of average dissolution
rate.
When a binder was not added at all (Comparative Example 2), there
was a large deviation in terms of average dissolution rate and thus
a stable in vivo dissolution of the preparation cannot be
expected.
EXPERIMENTAL EXAMPLE 3
Evaluation of Dissolution Pattern According to Compositions of the
Preparations
The dissolution patterns of the tablets manufactured via direct
compression in Examples 8 through 11 and Comparative Example 2 were
observed in purified water and compared with that of the control
drug. The results are shown in FIG. 1A. The conditions for the
evaluation of the dissolution were the same as provided in
Experimental Example 2.
The preparations of Examples 8 through 10 and Comparative Example 2
had dissolution rates of between 54.8% and 84.8% at the 15 min
determining point, and between 74.9% and 104.9% at the 30 min
determining point, thus being considered to be equivalent with that
of the drug on the market (according to the Notification No.
2013-201 of the Korean Ministry of Food and Drug Safety, when the
average dissolution rate of a drug on the market (reference drug)
reaches 85% between 15 min and 30 min, if the average dissolution
rate of a drug to be compared (test drug) is within that of the
reference drug .+-.15% at two different time points where the
average dissolution rate of the reference drug is around 60% and
85%, respectively, they can be determined as having
equivalence).
Meanwhile, the preparation of Example 11 showed a dissolution rate
of 55.9%, thus being equivalent, but at the 30 min determining
point, it showed a dissolution rate of 72.2%, which was lower than
the equivalent range of .+-.15%. Accordingly, the preparation is
not suitable for use as a solifenacin-containing preparation with
regard to biological equivalence.
The dissolution patterns of the preparations of Example 12 and
Comparative Example 3 were evaluated by comparing them with those
of the control drug. The results are shown in FIG. 1B. The
conditions for the evaluation of the dissolution were the same as
used in Experimental Example 2.
As a result of the evaluation, the preparation of Example 12 showed
a dissolution profile equivalent to that of the control drug.
However, the dissolution rate of the preparation of Comparative
Example 3 was outside of the range that could be considered as
determining equivalence to that of the control drug.
The dissolution pattern of the preparation of Example 13, which
contains 10 mg of solifenacin, was evaluated by comparing it with
that of the control drug, and was shown to have an equivalent level
of dissolution to that of the control drug (FIG. 2). The condition
for the evaluation of the dissolution was the same suggested in
Experimental Example 2.
As a result of the evaluation, it was confirmed that the
dissolution pattern of the preparation containing 10 mg of
solifenacin according to the present invention is equivalent to
that of the control drug.
EXPERIMENTAL EXAMPLE 4
Evaluation of Content Uniformity and Degree of Disintegration
Mass deviation and degree of disintegration among various
compositions in Examples were evaluated by comparison, and the
results are shown in Table 9 below. The preparations of Examples 8
through 11 and Comparative Example 2 were all manufactured to have
the same hardness.
TABLE-US-00009 TABLE 9 Evaluation Item Ex. 8 Ex. 9 Ex. 10 Ex. 11
Comp. Ex. 2 Hardness 7 .+-. 1 7 .+-. 1 7 .+-. 1 8 .+-. 3 7 .+-. 4
(KP) Mass 0.59 0.59 1.02 3.34 7.03 Deviation (%) Degree of 4 .+-. 1
.sup. 4 .+-. 1.5 6 .+-. 1 12 .+-. 2.5 .sup. 5 .+-. 3.8
Disintegration (min) Disintegration 9 .+-. 1 10 .+-. 2 11 .+-. 3 21
.+-. 4 12 .+-. 7 Time in a Medium at pH 6.8 (min)
The preparation of Example 11, to which a binder was added in the
amount of at least 30%, showed a larger tableting deviation
compared with those in other Examples, and also showed a larger
mass deviation compared with those in other Examples. In the case
of Comparative Example 2, which had no binder added at all, the
deviation relative to individual weight after tableting was shown
as large as being around average weight .+-.7%.
As a result of evaluating the degree of disintegration and
disintegration time in a phosphate buffer medium at pH 6.8
according to the types prepared, it was confirmed that the
preparation of Example 11 requires a considerable amount of time
for its dissolution. This implies that the preparation failed to
show a desirable dissolution pattern considering that solifenacin
succinate, as a main component, should be fast-released for rapid
therapeutic action.
Table 10 below shows the results of evaluation by comparison of
content uniformity of solifenacin succinate contained per each
tablet of the preparations in Example 12 and Comparative Example 3
relative to the control drug on the market (Vesicare.RTM. tablet).
The content uniformity test was performed according to the Content
Uniformity Test Method of the General Test Methods in the Korean
Pharmacopoeia (KP 10).
1) Diluent: a mixed solution of water/acetonitrile=7/3
2) Preparation of Test Solution: About one tablet was added into a
20 mL flask, filled up with the diluent up to about 80%, agitated
while occasionally shaking the flask until the test material was
disintegrated, and cooled at room temperature. The resultant was
added with the diluent to 20 mL and filtered through a 0.45 .mu.m
PVDF membrane filter to obtain a test solution.
3) Preparation of Standard Solution: 50 mg of a reference standard
of solifenacin succinate was accurately added into a 100 mL flask
and line-marked with the diluent to obtain a standard solution.
4) Operation and Calculation: 10 .mu.L each of the test solution
and the standard solution were subjected to the liquid
chromatography under the same operating condition as in the content
test, and the amount of solifenacin succinate was calculated via
the following equation.
.times..times..times..times..times..times..times..times..times..times..ti-
mes..times. ##EQU00001##
A.sub.T: Peak area of solifenacin succinate in the chromatogram of
a test solution
A.sub.S: Peak area of solifenacin succinate in the chromatogram of
a standard solution
W.sub.S: Amount of collection of a reference standard of
solifenacin succinate (mg)
C: Indicated amount of solifenacin succinate per one tablet of a
drug (mg)
P: Purity of a reference standard of solifenacin succinate (%)
D: Dilution fold (5)
TABLE-US-00010 TABLE 10 Comp. No. of Tests Ex. 12 Ex. 3 Control
Drug Test - 1 98.80 101.26 100.50 Test - 2 100.4 101.17 101.74 Test
- 3 100.8 95.95 98.63 Test - 4 100.6 99.42 100.90 Test - 5 101.9
98.10 99.66 Test - 6 103.9 97.24 97.52 Test - 7 104.1 95.31 100.24
Test - 8 100.1 96.46 99.69 Test - 9 100.8 95.68 100.01 Test - 10
100.0 96.46 101.68 Mean 101.1 97.71 100.06 Standard Deviation 1.70
2.21 1.30
As a result of the content uniformity test, it was confirmed that
the preparation of Example 12 manufactured via a direct compression
method by adding a binder had an equivalence in terms of
preparation uniformity and content in an individual tablet to that
of the control drug, and showed an improved result compared to the
composition not using a binder (Comparative Example 3) (the
recommended standard for solifenacin succinate content of the drugs
on the market is in the range of from 93.0% to 105.0%).
From the above results, it was found that a simple application of
the direct compression method can cause various problems in the
tableting process such as insufficient filling into dies of a
tablet press, a serious mass deviation due to separation of layers
or polarization within the granulated materials mixed therein,
content non-uniformity, sticking, capping, etc.
However, it was confirmed that the application of the compositions
of the present invention enables the manufacture of preparations,
which are expected to exhibit an in vivo dissolution at a degree
equivalent to that of the control drug without any problems such as
difficulty in tableting or mass deviation.
When the manufacture is performed using a high speed tableting
machine, in order to evaluate the effect on the content of the main
components, the composition of Example 12 was manufactured via high
speed tableting, and the content of solifenacin succinate according
to the tableting time was measured. The high speed tableting
machine used was an 8-station Piccolo rotary tablet press (RIVA),
wherein the turret was rotated at 25 rpm, and the tableted test
materials were randomly collected at the predetermined time for
measurement, and three tablets were selected therefrom and
subjected to a test for the average content. The tablets were
collected at initial time, 5, 10, 15, 30, 45, and 60 min, and the
collection was stopped thereafter. The test results are shown in
Table 11 below. The tablets manufactured via high speed tableting
showed no difference in content compared to those manufactured by a
single tableting machine.
TABLE-US-00011 TABLE 11 Collection Time of Tableted Standard
Material Test - 1 Test - 2 Test - 3 Mean Deviation Initial time
100.6 100.7 99.7 100.3 0.5 5 min after 100.3 101.0 99.8 100.4 0.6
high speed tableting 10 min after 101.6 99.9 97.5 99.7 2.1 high
speed tableting 15 min after 98.2 99.2 100.7 99.4 1.3 high speed
tableting 30 min after 99.4 100.3 97.9 99.2 1.2 high speed
tableting 45 min after 102.7 104.0 101.3 103.3 0.9 high speed
tableting 60 min after 102.2 97.5 98.3 99.3 2.5 high speed
tableting (termination)
* * * * *